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Mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the IspH enzyme

Here, we report an integrated quantum mechanics/molecular mechanics (QM/MM) study of the bio-organometallic reaction pathway of the 2H(+)/2e(–) reduction of (E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMBPP) into the so called universal terpenoid precursors isopentenyl pyrophosphate (IPP) and di...

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Autores principales: Abdel-Azeim, Safwat, Jedidi, Abdesslem, Eppinger, Jorg, Cavallo, Luigi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511988/
https://www.ncbi.nlm.nih.gov/pubmed/28757951
http://dx.doi.org/10.1039/c5sc01693b
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author Abdel-Azeim, Safwat
Jedidi, Abdesslem
Eppinger, Jorg
Cavallo, Luigi
author_facet Abdel-Azeim, Safwat
Jedidi, Abdesslem
Eppinger, Jorg
Cavallo, Luigi
author_sort Abdel-Azeim, Safwat
collection PubMed
description Here, we report an integrated quantum mechanics/molecular mechanics (QM/MM) study of the bio-organometallic reaction pathway of the 2H(+)/2e(–) reduction of (E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMBPP) into the so called universal terpenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), promoted by the IspH enzyme. Our results support the viability of the bio-organometallic pathway through rotation of the OH group of HMBPP away from the [Fe(4)S(4)] cluster at the core of the catalytic site, to become engaged in a H-bond with Glu126. This rotation is synchronous with π-coordination of the C2[double bond, length as m-dash]C3 double bond of HMBPP to the apical Fe atom of the [Fe(4)S(4)] cluster. Dehydroxylation of HMBPP is triggered by a proton transfer from Glu126 to the OH group of HMBPP. The reaction pathway is completed by competitive proton transfer from the terminal phosphate group to the C2 or C4 atom of HMBPP.
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spelling pubmed-55119882017-07-28 Mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the IspH enzyme Abdel-Azeim, Safwat Jedidi, Abdesslem Eppinger, Jorg Cavallo, Luigi Chem Sci Chemistry Here, we report an integrated quantum mechanics/molecular mechanics (QM/MM) study of the bio-organometallic reaction pathway of the 2H(+)/2e(–) reduction of (E)-4-hydroxy-3-methylbut-2-enyl pyrophosphate (HMBPP) into the so called universal terpenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), promoted by the IspH enzyme. Our results support the viability of the bio-organometallic pathway through rotation of the OH group of HMBPP away from the [Fe(4)S(4)] cluster at the core of the catalytic site, to become engaged in a H-bond with Glu126. This rotation is synchronous with π-coordination of the C2[double bond, length as m-dash]C3 double bond of HMBPP to the apical Fe atom of the [Fe(4)S(4)] cluster. Dehydroxylation of HMBPP is triggered by a proton transfer from Glu126 to the OH group of HMBPP. The reaction pathway is completed by competitive proton transfer from the terminal phosphate group to the C2 or C4 atom of HMBPP. Royal Society of Chemistry 2015-10-01 2015-06-22 /pmc/articles/PMC5511988/ /pubmed/28757951 http://dx.doi.org/10.1039/c5sc01693b Text en This journal is © The Royal Society of Chemistry 2015 https://creativecommons.org/licenses/by/3.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/ (https://creativecommons.org/licenses/by/3.0/) ) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Chemistry
Abdel-Azeim, Safwat
Jedidi, Abdesslem
Eppinger, Jorg
Cavallo, Luigi
Mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the IspH enzyme
title Mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the IspH enzyme
title_full Mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the IspH enzyme
title_fullStr Mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the IspH enzyme
title_full_unstemmed Mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the IspH enzyme
title_short Mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the IspH enzyme
title_sort mechanistic insights into the reductive dehydroxylation pathway for the biosynthesis of isoprenoids promoted by the isph enzyme
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511988/
https://www.ncbi.nlm.nih.gov/pubmed/28757951
http://dx.doi.org/10.1039/c5sc01693b
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